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FLT-PET Imaging of Radiation Responses in Murine Tumors

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Abstract

Background

3′-[F-18]Fluoro-3′-deoxythymidine (FLT) traces thymidine phosphorylation catalyzed by thymidine kinase during cell proliferation. Knowing the rate of cell proliferation during cancer treatment, such as radiation therapy, would be valuable in assessing whether tumor recurrence is likely and might indicate the need for additional treatments. However, the relationship between FLT kinetics and the effects of radiation is not well-understood. Nor has the method for optimal quantification of FLT uptake within the irradiated tumor microenvironment been extensively examined.

Materials and Methods

We performed dynamic FLT-positron emission tomography (PET) studies (60 min) on 22 mice implanted subcutaneously with syngeneic mammary MCaK tumors bilaterally in the shoulder area. A day before the FLT-PET imaging, the tumor on the right side was irradiated with a single dose (0, 2.5, 5, 10, or 20 Gy) or with fractionated exposures (4 × 2.5 Gy given in 12 h intervals). Standardized uptake value (SUVs) of FLT on tumors at 10 and 60 min post injection were calculated; model fitting was used to estimate the kinetic parameters. Significant radiation-induced changes were shown by comparing the irradiated tumor with the control tumor in the same animal and by comparing it to nonirradiated mice. The effect of radiation on MCaK cell cycle parameters and FLT uptake was also examined in vitro.

Results

In vivo FLT kinetics were sensitive to radiation doses of 5 Gy and higher (administered 1 day earlier), as judged by SUV semiquantitative measures and by modeling. Single irradiation with 10 Gy had greater impact on SUVs and kinetic parameters than fractionated exposures. Overall, the uptake constant K i appeared to be the best marker for these radiation effects. FLT uptake by irradiated cells in vitro at various doses gave similar findings, and the in vitro FLT uptake correlated well with K i . Radiation-induced G2/M arrest appeared to influence FLT uptake, and this was more pronounced after single than fractionated doses.

Conclusion

The kinetics of FLT uptake into murine mammary tumors was altered 1 day after radiation treatment. The dose-dependent response correlated well with in vitro FLT cellular uptake. Parameters (e.g., K i ) derived from FLT kinetics are expected to be useful for assessing the efficacy of irradiation treatment of tumors.

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Acknowledgement

The authors would like to thank Dr. Arion Chatziioannou and the staff in the small-animal imaging facility at Crump Institute for Molecular Imaging for performing the mouse PET imaging, Dr. Michael Kreissl for taking serial blood samples, and Dr. N. Satyamurthy and his staff in the UCLA medical cyclotron facility for producing the tracer FLT used in this study. This work was partly supported by DOE cooperative agreement DE-FC03-02ER63420, and by NIH grants RO1-EB001943 and P50-CA086306.

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Authors and Affiliations

  1. Department of Molecular and Medical Pharmacology, UCLA David Geffen School of Medicine, University of California in Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, 90095, USA

    M. H. Pan, S. C. Huang, Y. P. Liao & J. R. Barrio

  2. Department of Radiation Oncology, UCLA David Geffen School of Medicine, University of California in Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, 90095, USA

    D. Schaue, C. C. Wang, D. B. Stout & W. H. McBride

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  1. M. H. Pan
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  2. S. C. Huang
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Correspondence to S. C. Huang.

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Pan, M.H., Huang, S.C., Liao, Y.P. et al. FLT-PET Imaging of Radiation Responses in Murine Tumors. Mol Imaging Biol 10, 325–334 (2008). https://doi.org/10.1007/s11307-008-0158-z

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  • DOI: https://doi.org/10.1007/s11307-008-0158-z

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